I. Field of the Invention
The present invention relates to the fields of oncology and molecular biology. More particular the invention relates to the targeting of the Notch3 receptor.
II. Related Art
Lung cancer is the most common cause of cancer-related deaths in the United States. The cure rate for patients with lung cancer remains low—15%—and has not changed significantly during the past 30 years (Jermal et al., 2005). A better understanding of the signaling pathways important in driving and maintaining the malignant state allows the identification of new therapeutic targets and is thus imperative for continued progress in the treatment of these patients. Genes involved in cell fate determination often contribute to tumorigenesis when they are aberrantly expressed. The family of Notch receptors is one such family where there are now strong data linking it to cancer pathogenesis.
All four members of the Notch receptor family are known to be dysregulated in the majority of human cancers. The inventors were the first to link dysregulation of the Notch3 pathway to human lung cancer (Dang et al., 2000). They demonstrated that Notch3 is highly expressed in 40% of all resected lung cancers and that, in the developing lung, constitutive activation of Notch3 results in inhibition of terminal differentiation. Furthermore, they showed that inhibiting this pathway in human lung tumors results in the loss of the malignant phenotype in vitro and tumor inhibition in xenograft models. This anti-tumor effect is enhanced in the presence of low serum and in combination with an EGFr tyrosine kinase inhibitor. Taken together, these data support an important role for Notch3 and its interaction with the EGF and Ras pathways in lung cancer. However, methods for therapeutic intervention in Notch3 related cancers has not yet been reported.